Osteoarthritis of the Knee
Conditions
Brief summary
The main objective is the long-term comparison (3 years and 4 months) of the efficacy and safety of repeated intra-articular administration of hyaluronic acid in the treatment of osteoarthritis of the knee.
Detailed description
To evaluate the efficacy and safety of repeated injections of hyaluronic acid compared with placebo over a period of 40 months.
Interventions
DEVICEHyaluronic acid
3 cycles of 5 hyaluronic acid injections, with a 6 month interval between each one. A 4th treatment cycle of five injections will be carried out at the end of one year
OTHERPlacebo
3 cycles of 5 saline solution injections, with a 6 month interval between each one. A 4th treatment cycle of five injections will be carried out at the end of one year
Sponsors
Tedec-Meiji Farma, S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient \> 45 years of age * Out-patient diagnosed with primary osteoarthritis of the femorotibial medial joint of the knee with clinical and radiological (Kellgren grade II-III) ACR diagnosis * Joint Space Width (JSW) \> 2mm * Overall pain greater or equal to 55mm (VAS - Visual Analogue Scale 100mm) recorded in the knee,by the patient at any time during the week prior to the evaluation
Exclusion criteria
* Overweight patients (body mass index \> 32). * Pregnant and lactating women. Women of child-bearinge age not using effective contraception * Patients who have received intra-articular hyaluronic acid within the previous year and/or intra-articular steroids or articular lavage in the chosen knee,within the previous 3 months prior to their inclusion in the study. * AINE administration within the 14 days prior to their inclusion in the study. * Administration of glucosamine sulphate, chondroitin sulphate and diacerein within the 3 months prior to their inclusion in the study. * Immunocompromised patients or patients receiving systemic immunosuppressive therapy. * Patients with known sensitivity to HA, parcetamol or AINEs permitted as rescue medication. * Patients who have received any investigational drug within 30 days prior to visit 1, or who are scheduled for the administration of an investigational drug other than the protocol product during this study. * Patients with severely impaired central nervous system. * Patients with coagulation alterations, despite receiving treatment. * Patients with secondary osteoarthritis of the knee * Patients having previously received surgery, including arthroscopy * Patients with articular inflammatory disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Responders OARSI 2004 at the End of Follow-up | 40 months | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at the end of follow-up. Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Responders OARSI 2004 at 14 Months Follow-up Visit | 14 months (6 months after second cycle) | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 14 months follow-up visit (6 months after second cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. |
| Responders OARSI 2004 at 21 Months Follow-up Visit | 21 months (6 months after third cycle) | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 21 months follow-up visit (6 months after third cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. |
| Responders OARSI 2004 at 27 Months Follow-up Visit | 27 months (12 months after third cycle) | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 27 months follow-up visit (12 months after third cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. |
| Responders OARSI 2004 at 34 Months Follow-up Visit | 34 months (6 months after fourth cycle) | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 34 months follow-up visit (6 months after fourth cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. |
| Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up | 40 months | Percentage of patients with a decrease in pain or physical function score of at least 50% and at least 20mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome. |
| Responders OARSI 2004 at 7 Months Follow-up Visit | 7 months (6 months after first cycle) | Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 7 months follow-up visit (6 months after first cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome. |
| Function Improvement 20% (10mm) at the End of Follow-up | 40 months | Percentage of patients with a decrease in physical function score of at least 20% or at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome. |
| Patient's Global Assessment Increase 20% (10mm) at the End of Follow-up | 40 months | Percentage of patients with an increase in the score of patient's global assessment by at least 20% and at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a better outcome. |
| Percentage of Patients Who Consumed Rescue Medication for Osteoarthritis | Throughout the study, an average of 40 months | Consumption of rescue medication (paracetamol/NSAID) for osteoarthritis throughout the study, an average of 40 months |
| Mean Daily Dose of Paracetamol Consumption | Throughout the study, an average of 40 months | Mean daily dose of paracetamol consumption throughout the study, an average of 40 months |
| Overall Pain Reduction 20% (10mm) at the End of Follow-up | 40 months | Percentage of patients with a decrease in pain score of at least 20% or at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome. |
Participant flow
Recruitment details
Recruiting started in October 2003 and the last follow-up was performed on July 2009. This study enrolled patients from the Rheumatology Departments belonging to 19 centres located in Spain.
Pre-assignment details
A total of 446 patients were screened, of whom 140 (31,4%) were screening failures. At the screening visit the patients were assessed by the blinded physician for fulfilment of the selection criteria, demographic characteristics and medical history. Knee radiographs were also obtained.
Participants by arm
| Arm | Count |
|---|---|
| Hyaluronic Acid (Adant) Four cycles of 5 weekly intra-articular injections of 2.5ml 1% sodium hyaluronate with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles. | 153 |
| Placebo Four cycles of 5 weekly intra-articular injections of 2.5ml saline solution with a follow-up of 6 months after the first and second cycles, and 1 year after the third and fourth cycles. | 153 |
| Total | 306 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 16 |
| Overall Study | Lack of Efficacy | 8 | 19 |
| Overall Study | Lost to Follow-up | 6 | 5 |
| Overall Study | No fulfilment of the selection criteria | 5 | 5 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 13 |
Baseline characteristics
| Characteristic | Placebo | Total | Hyaluronic Acid (Adant) |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 8.9 | 63.4 years STANDARD_DEVIATION 8.6 | 63 years STANDARD_DEVIATION 8.2 |
| Body Mass Index (BMI) | 28.7 kg/m^2 STANDARD_DEVIATION 2.6 | 28.6 kg/m^2 STANDARD_DEVIATION 2.7 | 28.4 kg/m^2 STANDARD_DEVIATION 2.7 |
| Duration knee osteoarthritis | 8.1 years STANDARD_DEVIATION 8.4 | 7.5 years STANDARD_DEVIATION 7.6 | 6.9 years STANDARD_DEVIATION 6.8 |
| Sex: Female, Male Female | 128 Participants | 256 Participants | 128 Participants |
| Sex: Female, Male Male | 25 Participants | 50 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 153 | 11 / 153 |
| serious Total, serious adverse events | 0 / 153 | 0 / 153 |
Outcome results
Primary
Responders OARSI 2004 at the End of Follow-up
Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at the end of follow-up. Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome.
Time frame: 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Responders OARSI 2004 at the End of Follow-up | 80.5 percentage of responders |
| Placebo | Responders OARSI 2004 at the End of Follow-up | 65.8 percentage of responders |
p-value: 0.004Chi-squared
Secondary
Function Improvement 20% (10mm) at the End of Follow-up
Percentage of patients with a decrease in physical function score of at least 20% or at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome.
Time frame: 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Function Improvement 20% (10mm) at the End of Follow-up | 70.5 percentage of patients |
| Placebo | Function Improvement 20% (10mm) at the End of Follow-up | 57.9 percentage of patients |
p-value: 0.023Chi-squared
Secondary
Mean Daily Dose of Paracetamol Consumption
Mean daily dose of paracetamol consumption throughout the study, an average of 40 months
Time frame: Throughout the study, an average of 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hyaluronic Acid (Adant) | Mean Daily Dose of Paracetamol Consumption | 408.8 mg/day | Standard Deviation 644.2 |
| Placebo | Mean Daily Dose of Paracetamol Consumption | 451.4 mg/day | Standard Deviation 925.8 |
Secondary
Overall Pain Reduction 20% (10mm) at the End of Follow-up
Percentage of patients with a decrease in pain score of at least 20% or at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome.
Time frame: 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Overall Pain Reduction 20% (10mm) at the End of Follow-up | 79.2 percentage of patients |
| Placebo | Overall Pain Reduction 20% (10mm) at the End of Follow-up | 67.8 percentage of patients |
p-value: 0.025Chi-squared
Secondary
Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up
Percentage of patients with a decrease in pain or physical function score of at least 50% and at least 20mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a worse outcome.
Time frame: 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up | 65.1 percentage of patients |
| Placebo | Pain or Function Scores Reduction 50% (20mm) at the End of Follow-up | 52.0 percentage of patients |
p-value: 0.021Chi-squared
Secondary
Patient's Global Assessment Increase 20% (10mm) at the End of Follow-up
Percentage of patients with an increase in the score of patient's global assessment by at least 20% and at least 10mm on the VAS at the end of follow-up. The VAS is set between 0-100mm, higher values represent a better outcome.
Time frame: 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Patient's Global Assessment Increase 20% (10mm) at the End of Follow-up | 74.5 percentage of patients |
| Placebo | Patient's Global Assessment Increase 20% (10mm) at the End of Follow-up | 57.9 percentage of patients |
p-value: 0.002Chi-squared
Secondary
Percentage of Patients Who Consumed Rescue Medication for Osteoarthritis
Consumption of rescue medication (paracetamol/NSAID) for osteoarthritis throughout the study, an average of 40 months
Time frame: Throughout the study, an average of 40 months
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Percentage of Patients Who Consumed Rescue Medication for Osteoarthritis | 71.1 percentage of patients |
| Placebo | Percentage of Patients Who Consumed Rescue Medication for Osteoarthritis | 71.7 percentage of patients |
p-value: 0.9129Chi-squared
Secondary
Responders OARSI 2004 at 14 Months Follow-up Visit
Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 14 months follow-up visit (6 months after second cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome.
Time frame: 14 months (6 months after second cycle)
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Responders OARSI 2004 at 14 Months Follow-up Visit | 76.5 percentage of responders |
| Placebo | Responders OARSI 2004 at 14 Months Follow-up Visit | 65.1 percentage of responders |
p-value: 0.03Chi-squared
Secondary
Responders OARSI 2004 at 21 Months Follow-up Visit
Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 21 months follow-up visit (6 months after third cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome.
Time frame: 21 months (6 months after third cycle)
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Responders OARSI 2004 at 21 Months Follow-up Visit | 77.9 percentage of responders |
| Placebo | Responders OARSI 2004 at 21 Months Follow-up Visit | 67.8 percentage of responders |
p-value: 0.049Chi-squared
Secondary
Responders OARSI 2004 at 27 Months Follow-up Visit
Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 27 months follow-up visit (12 months after third cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome.
Time frame: 27 months (12 months after third cycle)
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Responders OARSI 2004 at 27 Months Follow-up Visit | 77.9 percentage of responders |
| Placebo | Responders OARSI 2004 at 27 Months Follow-up Visit | 67.8 percentage of responders |
p-value: 0.049Chi-squared
Secondary
Responders OARSI 2004 at 34 Months Follow-up Visit
Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 34 months follow-up visit (6 months after fourth cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome.
Time frame: 34 months (6 months after fourth cycle)
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Responders OARSI 2004 at 34 Months Follow-up Visit | 81.2 percentage of responders |
| Placebo | Responders OARSI 2004 at 34 Months Follow-up Visit | 65.1 percentage of responders |
p-value: 0.002Chi-squared
Secondary
Responders OARSI 2004 at 7 Months Follow-up Visit
Percentage of subjects with a clinical response according to Osteaorthritis Research Society International (OARSI) 2004 criteria at 7 months follow-up visit (6 months after first cycle). Patients were classified as responders if the pain or physical function scores decreased at least 50% and at least 20mm on the Visual Analogue Scale (VAS), or if two of the following three findings were recorded: a decrease in pain score of at least 20% or at least 10mm on the VAS, a decrease in physical function score of at least 20% and at least 10mm on the VAS, or an increase in the score of the patient's global assessment by at least 20% and at least 10mm on the VAS. The VAS is set between 0-100mm, higher values represent a worse outcome in all cases except for both patient and physician global assessments where higher values indicate a better outcome.
Time frame: 7 months (6 months after first cycle)
Population: The modified intention-to-treat population included all randomly assigned patients with at least one efficacy assessment after randomisation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hyaluronic Acid (Adant) | Responders OARSI 2004 at 7 Months Follow-up Visit | 71.1 percentage of responders |
| Placebo | Responders OARSI 2004 at 7 Months Follow-up Visit | 67.8 percentage of responders |
p-value: 0.525Chi-squared